scholarly journals CD36 deficiency ameliorates drug-induced acute liver injury in mice

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Chen Zhang ◽  
Xiao Shi ◽  
Zhongping Su ◽  
Chao Hu ◽  
Xianmin Mu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Protein Adducts ◽  
Sterile Inflammation ◽  
Inflammatory Factor ◽  
Cd36 Deficiency ◽  
Significant Difference

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.

scholarly journals S100A6 Promotes Inflammation and Infiltration of Mononuclear/Macrophages via the p-P38 and p-JNK Pathways in Acute Liver Injury

2021 ◽  
Author(s):  
He Tong ◽  
Li Wang ◽  
Kefan Zhang ◽  
Jing Shi ◽  
yongshuai Wu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
S100 Protein ◽  
Inflammatory Cells ◽  
Liver Cells ◽  
Danger Signal ◽  
Tnf Α

Abstract BackgroundThe phagocytic S100 protein, which mediates inflammatory responses and recruits inflammatory cells to sites of tissue damage, has long been known to be expressed in cells of myeloid origin. S100A6 belongs to the A group of the S100 protein family of Ca2+-binding proteins. Currently, the mechanism by which S100A6 mediates the inflammatory response and recruits inflammatory cells to the tissue injury site is unknown.MethodsA mouse model of carbon tetrachloride (CCl4)-induced acute liver injury (ALI) was established, and the transcriptomes of postinjury 2d and 5d liver tissues were sequenced. Enzyme-linked immunosorbent assay was used to determine the expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8) in the supernatant of the liver. Immunohistochemical analysis confirmed the expression of S100A6 in the liver cells. In vitro experiments proved the pro-inflammatory function of S100A6, and western blotting (WB) showed that the pathways were activated. The transwell experiment showed the infiltration of mononuclear/macrophages.ResultsWe found that S100A6 is highly expressed in liver cells during the most severe period of ALI, suggesting that it acts as an endogenous danger signal and has a pro-inflammatory function. In vitro, the mouse S100A6 recombinant protein was used to stimulate liver Kupffer cells to promote the secretion of TNF-α, IL-1β, IL-6, and IL-8. Further mechanistic experiments revealed that S100A6 acts as an endogenous danger signal to activate p-P38 and p-JNK downstream of the TLR4 and P65 pathways. Similarly, transcriptome data showed that S100A6 can activate the inflammatory response in Kuffer cells. WB revealed that S100A6 had no significant effect on cell apoptosis. To continue to explore the mechanism of monocyte/macrophage infiltration, we found that TNF-α stimulates liver cells as the main source of CCL2. TNF-α can initiate the p-P38 and p-JNK pathways of liver cells to produce CCL2, thereby recruiting the infiltration of mononuclear/macrophages. ConclusionsTaken together, S100A6 is an endogenous danger signal that mediates inflammatory responses and recruits inflammatory cells to sites of tissue damage.

scholarly journals The protein tyrosine kinase SYK regulates the alternative p38 activation in liver during acute liver inflammation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bo-Ram Bang ◽  
Kyung Ho Han ◽  
Goo-Young Seo ◽  
Michael Croft ◽  
Young Jun Kang
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Host Defense ◽  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Critical Role ◽  
Liver Inflammation ◽  
Hepatocyte Death

AbstractTwo distinct p38 signaling pathways, classical and alternative, have been identified to regulate inflammatory responses in host defense and disease development. The role of alternative p38 activation in liver inflammation is elusive, while classical p38 signaling in hepatocytes plays a role in regulating the induction of cell death in autoimmune-mediated acute liver injury. In this study, we found that a mutation of alternative p38 in mice augmented the severity of acute liver inflammation. Moreover, TNF-induced hepatocyte death was augmented by a mutation of alternative p38, suggesting that alternative p38 signaling in hepatocytes contributed more significantly to the pathology of acute liver injury. Furthermore, SYK-Vav-1 signaling regulates alternative p38 activation and the downregulation of cell death in hepatocytes. Therefore, it is suggested that alternative p38 signaling in the liver plays a critical role in the induction and subsequent pathological changes of acute liver injury. Collectively, our results imply that p38 signaling in hepatocytes plays a crucial role to prevent excessive liver injury by regulating the induction of cell death and inflammation.

scholarly journals Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nao Hasuzawa ◽  
Keita Tatsushima ◽  
Lixiang Wang ◽  
Masaharu Kabashima ◽  
Rie Tokubuchi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Degradation Products ◽  
Purinergic Signaling ◽  
Atp Release ◽  
High Cholesterol Diet ◽  
Deficient Diet ◽  
Triglyceride Accumulation ◽  
Therapeutic Benefits

AbstractThe vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.

scholarly journals Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury

2021 ◽  
Vol 135 (7) ◽  
pp. 925-941
Author(s):  
Yanjun Liu ◽  
Jiacheng Li ◽  
Liping Liao ◽  
Heming Huang ◽  
Shijie Fan ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Diseases ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Stellate Cell ◽  
Cyclin Dependent Kinase ◽  
Liver Inflammation ◽  
Public Health Burden

Abstract Liver diseases present a significant public health burden worldwide. Although the mechanisms of liver diseases are complex, it is generally accepted that inflammation is commonly involved in the pathogenesis. Ongoing inflammatory responses exacerbate liver injury, or even result in fibrosis and cirrhosis. Here we report that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, exerts beneficial effects on acute and chronic liver inflammation as well as fibrosis. Animal models of lipopolysaccharide (LPS)/d-galactosamine- and acute or chronic CCl4-induced liver injury showed that roscovitine administration markedly attenuated liver injury, inflammation and histological damage in LPS/d-galactosamine- and CCl4-induced acute liver injury models, which is consistent with the results in vitro. RNA sequencing (RNA-seq) analysis showed that roscovitine treatment repressed the transcription of a broad set of pro-inflammatory genes involved in many aspects of inflammation, including cytokine production and immune cell proliferation and migration, and inhibited the TGF-β signaling pathway and the biological process of tissue remodeling. For further validation, the beneficial effect of roscovitine against inflammation was evaluated in chronic CCl4-challenged mice. The anti-inflammation effect of roscovitine was observed in this model, accompanied with reduced liver fibrosis. The anti-fibrotic mechanism involved inhibition of profibrotic genes and blocking of hepatic stellate cell (HSC) activation. Our data show that roscovitine administration protects against liver diseases through inhibition of macrophage inflammatory actions and HSC activation at the onset of liver injury.

scholarly journals IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Lujing Shao ◽  
Xi Xiong ◽  
Yucai Zhang ◽  
Huijie Miao ◽  
Yuqian Ren ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Mrna Levels ◽  
Protective Effects ◽  
Activating Transcription Factor 4 ◽  
Pre Treatment ◽  
Underlying Mechanisms

Abstract Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593–0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/−) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.

scholarly journals miR-23b Negatively Regulates Sepsis-Induced Inflammatory Responses by Targeting ADAM10 in Human THP-1 Monocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Wenying Zhang ◽  
Furong Lu ◽  
Yuliu Xie ◽  
Yao Lin ◽  
Tian Zhao ◽  
...  
Keyword(s):  
Western Blot ◽  
Inflammatory Cytokines ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Annexin V ◽  
Luciferase Reporter ◽  
Inflammatory Factor ◽  
Bioinformatics Analyses ◽  
Peripheral Blood Mononuclear ◽  
Adam10 Expression

Background. Previous studies have demonstrated pivotal roles of disintegrin and metalloproteinase 10 (ADAM10) in the pathogenesis of sepsis. MicroRNA- (miR-) 23b has emerged as an anti-inflammatory factor that prevents multiple autoimmune diseases. However, the underlying mechanisms of miR-23b in the regulation of ADAM10 and sepsis remain uncharacterized. Methods. The expression levels of ADAM10 and miR-23b were detected by quantitative RT-PCR and western blot analysis. Cytokine production and THP-1 cell apoptosis were measured by enzyme-linked immunosorbent and annexin V apoptosis assays. Bioinformatics analyses and qRT-PCR, western blot, and luciferase reporter assays were performed to identify ADAM10 as the target gene of miR-23b. Results. miR-23b expression was downregulated in the peripheral blood mononuclear cells of sepsis patients and LPS-induced THP-1 cells and was negatively correlated with the expression of ADAM10 and inflammatory cytokines. miR-23b regulated ADAM10 expression by directly binding to the 3′-UTR of ADAM10 mRNA. The overexpression of miR-23b alleviated the LPS-stimulated production of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and apoptosis by targeting ADAM10 in THP-1 cells. The inhibitor or knockdown of ADAM10 elicited effects similar to those of miR-23b on THP-1 cells upon LPS stimulation. Conclusions. The present study demonstrated that miR-23b negatively regulated LPS-induced inflammatory responses by targeting ADAM10. The molecular regulatory mechanism of miR-23b in ADAM10 expression and sepsis-induced inflammatory consequences may provide potential therapeutic targets for sepsis.

scholarly journals Early identification using the referral system prolonged the time to onset for hepatic encephalopathy after diagnosing severe acute liver injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Keisuke Kakisaka ◽  
Yuji Suzuki ◽  
Hiroaki Abe ◽  
Takuya Watanabe ◽  
Kenji Yusa ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Hepatic Encephalopathy ◽  
Liver Injury ◽  
Early Identification ◽  
Total Bilirubin ◽  
Acute Liver Injury ◽  
Referral System ◽  
Significant Difference ◽  
Risk Of Progression ◽  
Time To Onset

Abstract In 2004, we implemented a referral system for patients with acute liver injury (ALI) based on an established formula that estimates the risk of progression to acute live failure (ALF); however, the benefits of the system for patients with severe acute liver injury (SLI) remain unclear. We have evaluated the clinical significance of the referral system for SLI patients. Patients with ALI/SLI who were consecutively and prospectively listed on the system between 2004 and 2018 were analyzed. Of the 371 ALI/SLI/ALF patients on the system, 124 satisfied the criteria for SLI; 34 of these 124 progressed to SLI after registration. Multivariate analysis using age, sex, AST, ALT, creatinine, total bilirubin, prothrombin, presence of hepatic encephalopathy (HE), and SLI at registration revealed that HE was associated with high mortality. Among the 23 patients who developed HE, five who progressed to SLI after registration showed an increased time to HE development compared with patients who had SLI at the time of registration. However, there was no significant difference in survival time after HE development. We concluded that early identification of SLI patients using the referral system increased the time from SLI diagnosis to HE development.

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